Optimizing Large Language Models for Causality Assessment in Pharmacovigilance: Developing a Performance Metric as Objective for Bayesian Hyperparameter Optimization
Authors: Nicole Sonne Heckmann, Arnault-Quentin Vermillet, Søren Norlin Mølgaard, Manuela Del Castillo Suero, Lars Melskens, Gerard Ompad, Maurizio Sessa
Background: Growing individual case safety report (ICSR) volumes have intensified demand for scalable automated causality assessment. Large Language Models (LLMs) show promise, yet performance on clinically demanding tasks remains suboptimal and inference-time hyperparameter optimization has not been investigated. Objective: To develop a Gaussian Process (GP)-compatible optimization objective and investigate whether temperature optimization improves LLM-expert agreement on Naranjo causality assessment of FAERS ICSRs. Methods: Expert causality assessments were performed on 723 stratified FAERS cases. OpenAI's GPT-5.2 was evaluated using chain-of-thought (CoT) prompting. Four composite metrics were developed: Weighted Cosine Similarity (WCS), Information-Weighted Agreement Score (IWAS), Entropy-Weighted Agreement and Cosine Similarity Score (EWACS), and Consensus-Weighted Cosine Similarity (CWCS) and Bayesian optimization using a GP surrogate with Probability of Improvement (PoI) acquisition was applied across temperature [0, 2]. Results: GPT-5.2 outperformed prior biomedical LLMs at baseline (T = 0), achieving 74.1% agreement on question 5 and 65.4% on question 10 of Naranjo algorithm. Entropy analysis identified these as the sole informative optimization targets. Temperature showed no systematic population-level effect (\b{eta} = 0.002, p = 0.959). EWACS-guided Bayesian optimization improved causality classification agreement from 45.0% to 72.0% (+27 pp), with the largest gain in Doubtful cases (+42.9 pp). Conclusion: EWACS was identified as the optimal GP-compatible metric. The absence of a universal temperature optimum indicates LLM performance is driven primarily by ICSR content, yet case-specific temperature selection produced meaningful improvements, supporting temperature optimization for LLM-assisted pharmacovigilance.
The ability to understand causality significantly impacts the competence of large language models (LLMs) in output explanation and counterfactual reasoning, as causality reveals the underlying data distribution. However, the lack of a comprehensive benchmark currently limits the evaluation of LLMs' causal learning capabilities. To fill this gap, this paper develops CausalBN-Bench based on data from the causal research community, enabling comparative evaluations of LLMs against traditional causal learning algorithms. To provide a comprehensive investigation, we offer three tasks of varying difficulties, including correlation, causal skeleton, and causality identification. Evaluations of 19 leading LLMs reveal that, while closed-source LLMs show potential for simple causal relationships, they significantly lag behind traditional algorithms on larger-scale networks (>50 nodes). Specifically, LLMs struggle with collider structures but excel at chain structures, especially at long-chain causality analogous to Chain-of-Thought techniques. This supports the current prompt approaches while suggesting directions to enhance LLMs' causal reasoning capability. Furthermore, CausalBN-Bench incorporates background knowledge and training data into prompts to thoroughly unlock LLMs' text-comprehension ability during evaluation, whose findings indicate that, LLM understand causality through semantic associations with distinct entities, rather than directly from contextual information or numerical distributions.
Causal discovery is a cornerstone of scientific reasoning, yet whether large language models can perform it reliably remains an open question. Recent benchmarks show that even fine-tuned models plateau on simple causal graphs and degrade as complexity grows, but why they fail has not been established. We prove the failure is fundamental: supervised fine-tuning, direct preference optimization, and in-context learning all produce predictors that cannot distinguish between causal graphs generating similar observational data, and any attempt to do so requires the model's internal representations to grow unboundedly, violating the very conditions under which these methods work. We formalize this as a kernel obstruction theorem, establishing that the limitation is intrinsic to the learning paradigm, \emph{not any particular model or dataset}. We propose Agentic Causal Bayesian Optimization (A-CBO), wherein a frozen language model serves as an interventional oracle answering targeted queries about intervention effects, while an external Bayesian loop concentrates beliefs over candidate graphs in logarithmically many rounds. Because the decision operates outside the space where the obstruction applies, A-CBO provably converges while the underlying model remains unchanged. On Corr2Cause, A-CBO matches fine-tuned baselines without any training. On Extended Corr2Cause, a new benchmark scaling to 24 variables with 18K test samples, A-CBO significantly outperforms both fine-tuning and preference optimization, with the advantage growing
Large language models (LLMs) are increasingly integrated into decision-support roles in business and policy contexts. While prior benchmark studies have primarily evaluated LLMs' causal reasoning capabilities, a more fundamental epistemic dimension has been overlooked: Causal Caution, defined as the propensity to refrain from causal judgment when empirical evidence is insufficient. This study examines the systematic suppression of Causal Caution that occurs when LLMs shift from academic to practical advisory contexts. Using an evaluation rubric inspired by Pearl's Causal Hierarchy (the PCH score), we conducted experiments on four high-performance LLMs -- Claude Sonnet 4.6, Claude Opus 4.7, GPT 5.5, and Gemini 3.1 Pro -- across 480 trials. Causal Caution maintenance rates were 91.7--100.0% in academic contexts but dropped to 6.7--18.3% in practical advisory contexts (Fisher's exact test, p < .001 across all models). Furthermore, when restricted to practical prompts requesting concrete recommendations or explanatory rationales, only 1 of 200 responses (0.5%) maintained Causal Caution. A brief self-correction prompt -- "Please reconsider this judgment from the perspective of causal relationships" -- restored the expression of Causal Caution to maintenance rates of 71.4--100.0% (McNemar's test, p < .001 across all models). These results suggest that helpfulness-oriented response patterns may suppress the expression of Causal Caution in practical advisory contexts, with important implications for organizational governance. The findings indicate that this suppression reflects context-dependent variation in expression rather than an underlying capability limitation, suggesting that multi-agent architectures that separate proposal generation from causal auditing may offer a promising governance design.